The overall goal is to demonstrate a link between mercury (Hg) exposure and elevated risks of autoimmune disease. In this project, we will test two hypotheses in translational research linking basic research in an animal model of autoimmune disease and a pilot epidemiological study in a Hg-exposed human population in Amazonian Brazil. The hypotheses are that 1) exposure of mice (adults and fetuses) to Hg, at low dose, can result in changes in the innate immune response to infection such that ultimately post-infection autoimmune disease is exacerbated in terms of severity and prevalence and 2) exposure of humans to Hg, at low dose, can result in changes in the immune system that are measurable and indicative of elevated risk of autoimmune dysfunction. Autoimmune diseases are among the most devastating chronic diseases in the US, affecting nearly 50 million people. While autoimmune diseases are generally recognized to involve both heritable and acquired risk factors, relatively little is known about the latter risks for human disease aside from exposure to infectious agents, such as viruses and bacteria. These infectious agents are believed to trigger the development of autoimmune diseases, but the expressio'n and severity of disease may be a reflection of pre-existing genetic susceptibility. This project will assess programming changes that occur during the innate immune response to infection following exposure (either at adulthood or during fetal development) to Hg, with an overall effect on the progression of Coxsackievirus-induced autoimmune heart disease in mice and apply the biomarkers mined from the studies in animals to a Hg-exposed human population in Amazonian Brazil. Specific Aim 1. To test the hypothesis that Adult (murine) exposure to Hg induces changes in the innate immune response to Coxsackievirus infection, which result in exacerbation of subsequent autoimmune heart disease. Specific Aim 2. To test the hypothesis that Fetal (murine) exposure to Hg induces changes in the immune system that are long lasting and that these early events affect the innate immune response to Coxsackievirus infection and the subsequent development of autoimmune heart disease in adulthood. Specific Aim 3. To test the hypothesis that: Human exposure to Hg induces changes in the immune system that are measurable and indicative of elevated risk of autoimmune dysfunction.